Method for the production of derivatives of cyclic beta-keto carboxylic acids



Patented Jan. 19, 1937 UNITED STATES PATENT OFFICE METHOD FOR THE PRODUCTION OF DE- RIVATIVES OF CYCLIC fi-KETO CARBOX- YLIO ACIDS Karl Ziegler, Heidelberg, Germany, assignor to Schering-Kahlbaum A. G., Berlin, Germany, a corporation of Germany No Drawing.

Application November 16, 1934,

Serial No. 753,303. In Germany November 18,

16 Claims.

with condensing agents of the type N mM wherein R1 and R2 indicate an alkyl, aralkyl, aryl,

or an alicyclic radical, M an alkali, alkaline earth,

or earth metal, as for instance Li, Na, Mg, or Al, and m the valency of said metal and in saponifying the u-cyano ketimides formed, if required. In the book by K. A. Hofmann entitled Lehrbuch der Anorganischer Chemie, sixth edition, 1928, page 476, the earth metals are defined as including in addition to aluminum, those metals, the oxides of which are designated as rare earths.

Now, it has been found that, in order to successfully carry out the cyclization, it is essential to use a condensing agent of the type Rf wherein R1 is an aromatic, R2 a non-aromatic radical, M an alkali metal, in homogeneous solution and preferably in a concentration being near to the concentration of saturation or even in saturated solution while the dinitrile to be cyclized, is kept in the reaction mixture continuously in a concentration as low as possible, as stated in the main application.

Furthermore, it has been found that the yield of cyclic cyano-ketimides under otherwise comparable conditions is the better, the higher the atomic number of the used alkali metal is.

These conditions will be explained in detail by the following experiments which were carried out in the following manner:

3 liters of an ethereal condensing agent are heated under reflux to boiling thereby excluding the presence of air. 'Ihereupon a solution of 0.2 mols of the dinitriles with 16 or 18 carbon atoms in ether was allowed to flow within '72 hours continuously into the first named solution; thereupon the reaction mixture is decomposed by water and the ether is evaporated; the amine formed is then distilled off with steam.

The non-volatile residue represents the crude u-cyanoketimide.

For determining the yield of the cyclic product it proved to be expedient to saponify the crude ketimide to the corresponding cyclic ketone by boiling the former for 5 hours with 70% sulfuric,

acid and to isolate the ketones in a suitable manner, for instance, by distillation with superheated steam.

The following table contains the results.

Yield oi Condensing agent Moi/1 Ketone O1 Ketone O11 Percent Percent L1-ethyl an1l1de 0. 14 22 33 D0 0. 7 33 45 erably a greater excess of the reagent is to be em ployed.

Since by said modification of the method of the main application the yield can be increased to almost three times the yield obtained when producing derivatives of the 15-membered ring system according to the process of the main patent and to more than twice the yield obtained when producing derivatives of the 17 membered ring system, it represents a considerable technical advance.

The new knowledge can furthermore be made use of in another manner in order to technically simplify the method described in the main patent application Serial No. 684,233.

It was realized that it is very important, that,

the dinitrile when synthesizing compounds with more than six ring members has always to be present in the reaction mixture in a very low concentration; this is usually achieved by causing the dinitrile to flow very slowly into the condensing agent. Said flowing-in of the dinitrile into the condensing agent, however, requires often several days,

When, for instance, under the above mentioned conditions at a concentration of 0.14 n lithium ethyl-anilide a yield of 33-35% of the theoretical amount of the cyanoketimide with 15 ring members is to be achieved, a time of reaction of 14 days is necessary. On the other hand, with a 0.7 21 solution of the condensing agent the same result is obtained in 3 days.

Hence, this invention-can be made use of first to increase the yield in the same period of time of reaction and furthermore to produce the same yields in a substantially shorter period of time, a fact which is of great importance for technically carrying out this process.

Example 1 An ethereal solution of sodium methylanilide is produced from 20 grams of metallic sodium, 56 grams of naphthalene and 116 grams of methyl aniline in 1.3 liters of absolute ether.

A solution of 21 grams of tridecane-1,13-dicarboxylic acid dinitrile (melting point 31-31.5 C.) is caused to run into said first solution within a'period of '72 hours while vigorously boiling and stirring. After decomposition with water a clear, yellowish solution-is obtained from which, after distilling oif the ether, methylaniline and dihydro naphthalene are removed by blowing 011 with steam. The residue which is at first resinous, solidifies on triturating with ether and yields after filtering by suction 10.3 grams of l-cyano tetradecanone imide-(Z) in the form of colorless crystals of the melting point 147-148" C. (recrystallized from acetic acid ester). The mother liquors retain some of the product in mixture with other resins. In order to determine the total yield, they are boiled for 5 hours with 70%. sulfuric acid and are distilled with steam. Thereby 1.85 grams of cyclotetradecanone of the melting point 53 C. are recovered so that the total yield of the cyclization product amounts to about 62%.

Example 2 An ethereal solution of sodium isoamyl anilide is produced from 46 grams of sodium, 128 grams of naphthalene, 380 grams of isoamyl aniline and 4 liters of ether. A solution of 23 grams of pentadecane-l,l5-dicarboxylic acid nitrile (melting point ill-41 C.) in 300 cc. of ether is allowed to flow into said first-named solution within 32 hours.

The obtained cyanoketimide which contains a lfi-membered ring, crystallizes with difliculty. Hence, in order to determine the yield it is directly saponified by heating for 5 hours with 70% sulfuric acid. On consecutive steam distillation 16.12 grams of cyclohexadecanone are obtained, i. e. 77% the theoretical amount.

Example 3 In the same manner as described in Examples 1 and 2 azelaic acid dinitrile is transformed into,

oyano cyclo-octanone imide, whereby the yield amounts to about of the theoretical amount.

ance with the principles set forth herein and in the claims annexed hereto.

What I claim, is:

1. A method of producing cyclic u-cyanketone compounds consisting in acting on a nitrile having the formula GEN K fin OHr-OEN n being an integer, with a condensing agent of the type NM RI wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, while M compounds consisting in acting on a nitrile hav-' ing the formula CHr-CEN n being an integer, with a condensing agent 01 the type N-M R:

wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, while M is an alkali metal, the concentration of said condensing agent in solution being kept essentially at the point of saturation during the reacton.

4. A method of producing cyclic a-cyanoketone compounds consisting in acting on a nitrile having the formula GEN M CEr-CEN n being an integer, with a condensing agent of the type wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radicalwhile M is an alkali metal, the concentration of said condensing agent in solution being kept essentially at the point of saturation during the reaction, while the concentration of the dinitrile to be reacted in the reaction mixture is kept as low as possible during the reaction.

5. A method of producing cyclic a-cyanoketone compounds "consisting in acting on a nitrile having the formula GEN (C1191:

GHQ- JEN n being an integer, with a condensing agent of the type wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical.

6. A method of producing cyclic a-cyanoketone compounds consisting in acting on a nitrile having the formula GEN CHr-CEN n being an integer, with a condensing agent of the type N-Na wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, the con-- centration of said condensing agent in solution being kept essentially at the point of saturation during the reaction.

7. A method of producing cyclic a-cyanoketone compounds consisting in acting on a nitrile having the formula n being an integer, with a condensing agent of the type NNa wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, the concentration of said condensing agent in solution being essentially at thepoint of saturation during the reaction, while the concentration of the di-nitrile to be reacted in the reaction mixture is kept as low as possible during the reaction.

8. A method 7 of producing cyclic u-cyano-- ketone compounds consisting in acting on a nitrile having the formula GEN GHQ-GEN n being an integer, with a condensing agent of the type R1 NM R,

wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, while M is an alkali metal, decomposing the reaction mixture with water and isolating the resulting cyanoketimide.

9. A method of producing cyclic a-cyanoketone compounds consisting in preparing an essentially saturated solution of a condensing agent of the type R2 wherein R1 represents an aromatic and R2 a nonaromatic organic, alkyl or alicyclic radical while M is an alkali metal, in an indifferent organic solvent, allowing a solution of a dinitrile having the formula GEN CHa-CEN being an integer, in the same solvent, to flow gradually, uniformly and slowly into said solution of the condensing agent while vigorously boiling and stirring, decomposing the reaction mixture with water and isolating the resulting cyanoketimide.

10. A method of producing cyclic a-cyanoketone compounds consisting in acting on a nitrile having the formula GEN ( fl)n CHr-CEN n being an integer, with a condensing agent of the type /NM a wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, while M is an alkali metal, decomposing the reaction mixture with water, isolating the resulting cyanoketimide and saponifying the same with an agent which is suificiently mild to change the imido group into a keto group without saponifying the cyano group.

11. A method of producing cyclic u-cyanoketone compounds consisting in acting on a nitrile having the formula GEN (OHfln CHd-CEN n being an integer, with a condensing agent of the type Wherein R1 is an aromatic and R2 a non-aromatic organic, alkyl or alicyclic radical, While M is an alkali metal, decomposing the reaction mixture with water, heating the resulting reaction product with 70% sulfuric acid and isolating the saponification product.

13. The a-cyanocycloketimides of the general formula V G=NH (CHa)n wherein n denotes an integer which is 5 or greater.

14. The a-cyanocyclotetradecanone imide of the structural formula o=NH (CHDH CH-CEN which crystallizes from acetic acid ester in the form of colorless crystals of the melting point 147-148 C. I

15. The a-cyanocyclo'octanone imide of the structural formula 5 /C=VNH (C 1): I

H-CEN which forms colorless crystals of the melting 10 point 106-107 C.

16. The acyanocyclohexadecanone imide of the structural formula /C=NH (CH:)14 15 CHI-GEN which crystallizes with difliculty.

KARL ZIEGLER. 

